Download PRODUCT INFORMATION Elaxine SR 37.5, Elaxine SR 75, and

PRODUCT INFORMATION
Elaxine® SR 37.5, Elaxine® SR 75, and Elaxine® SR 150
(Modified release capsules)
NAME OF THE MEDICINE
Proprietary names: Elaxine SR 37.5, Elaxine SR 75 and Elaxine SR 150
Non proprietary name: Venlafaxine (as hydrochloride) 37.5 mg, 75 mg and 150 mg
modified release capsules.
The full chemical name for Venlafaxine hydrochloride is 1-[(R/S)-2-(2-dimethylamino)1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride.
Its molecular weight is 313.9 and its molecular formula is C17H27NO2,HCl.
Its chemical structure is:
CAS Number: 99300-78-4
DESCRIPTION
Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of
572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride).
Elaxine SR capsules are a modified release formulation, which release the active
constituent, venlafaxine hydrochloride, from mini-tablets within the capsule. Drug release
is controlled by diffusion through the coating on the mini-tablets and is not pH
dependent. Three strengths of Elaxine SR capsules are available containing 37.5 mg, 75
mg or 150 mg of venlafaxine (as hydrochloride).
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Other ingredients are – microcrystalline cellulose, povidone, purified talc, colloidal
anhydrous silica, magnesium stearate, ethylcellulose and copovidone. For each strength,
the capsule shells contain:
37.5 mg: gelatin, titanium dioxide, iron oxide black E172, iron oxide red E172 and iron
oxide yellow E172. The printing uses TekPrint SB-1033 Red Ink (Proprietary ingredient
ID 106948).
75 mg: gelatin, titanium dioxide, iron oxide black E172 and iron oxide red E172. The
printing uses TekPrint SB-1033 Red Ink (Proprietary ingredient ID 106948).
150 mg: gelatin, titanium dioxide, Brilliant Blue FCF E 133, Allura Red AC E 129 and
Sunset Yellow FCF E 110. The printing uses TekPrint SB-0007P White Ink (Proprietary
ingredient ID 2216).
PHARMACOLOGY
Actions
Venlafaxine is a structurally novel antidepressant for oral administration; it is chemically
unrelated to tricyclic, tetracyclic, or other available antidepressant agents.
The antidepressant action of venlafaxine in humans is believed to be associated with its
potentiation of neurotransmitter activity in the central nervous system. Preclinical studies
have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV),
are potent inhibitors of serotonin and noradrenaline reuptake, and also weakly inhibit
dopamine reuptake. Venlafaxine is a racemate. The R-enantiomer is relatively more
potent than the S-enantiomer with regard to inhibition of noradrenaline reuptake; the Senantiomer is more potent regarding serotonin reuptake. Both enantiomers are more
potent on serotonin compared to noradrenaline reuptake. The enantiomers of ODV also
inhibit both noradrenaline and serotonin reuptake, with the R-enantiomer being more
potent. Venlafaxine and its major metabolite appear to be equipotent with respect to their
overall action on neurotransmitter re-uptake and receptor binding. Studies in animals
show that tricyclic antidepressants may reduce β-adrenergic receptor responsiveness
following chronic administration. In contrast, venlafaxine and ODV reduce β-adrenergic
responsiveness after both acute (single dose) and chronic administration.
Venlafaxine has no significant affinity for rat brain muscarinic, H1-histaminergic or α1adrenergic receptors in vitro. Pharmacological activity at these receptors is potentially
associated with various sedative, cardiovascular, and anticholinergic effects seen with
other psychotropic drugs. Venlafaxine does not possess monoamine oxidase (MAO)
inhibitory activity.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate,
benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.
Venlafaxine also does not produce noradrenaline release from brain slices. It has no
significant central nervous system (CNS) stimulant activity in rodents. In primate drug
discrimination studies, venlafaxine showed no significant stimulant or depressant abuse
liability.
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Pharmacokinetics
Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral
multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose
range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and
ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2
and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is
7.5±3.7 and 5.7±1.8 L/kg, respectively.
Absorption
On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is
absorbed, indicating that absorption of venlafaxine is nearly complete. However, the
presystemic metabolism of venlafaxine (which primarily forms the active metabolite,
ODV) reduces the absolute bioavailability of venlafaxine to 42%±15%.
After administration of venlafaxine modified release (150 mg q24 hours), the peak
plasma concentrations (Cmax) of venlafaxine (150 ng/mL) and ODV (260 ng/mL) were
attained within 6.0±1.5 and 8.8±2.2 hours, respectively. The rate of absorption of
venlafaxine from the venlafaxine modified release capsule is slower than its rate of
elimination. Therefore, the apparent elimination half-life of venlafaxine following
administration of venlafaxine modified release (15±6 hours) is actually the absorption
half-life instead of the true disposition half-life (5±2 hours) observed following
administration of an immediate-release tablet.
When equal doses of venlafaxine, administered either as an immediate-release tablet
taken in divided doses or as a modified-release capsule, were taken once a day, the
exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was
similar for the two treatments, and the fluctuation in plasma concentrations was slightly
lower following treatment with the venlafaxine modified release capsule. Therefore, the
venlafaxine modified release capsule provides a slower rate of absorption, but the same
extent of absorption (i.e., AUC), as the venlafaxine immediate-release tablet.
No accumulation of venlafaxine or ODV has been observed during chronic
administration in healthy subjects.
Distribution
The degree of binding of venlafaxine to human plasma proteins is 27%±2% at
concentrations ranging from 2.5 to 2215 ng/mL, and the degree of ODV binding to
human plasma proteins is 30%±12% at concentrations ranging from 100 to 500 ng/mL.
Protein-binding-induced drug interactions with concomitantly administered venlafaxine
are not expected. Following intravenous administration, the steady-state volume of
distribution of venlafaxine is 4.4±1.9 L/kg, indicating that venlafaxine distributes well
beyond the total body water.
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Metabolism
Following absorption, venlafaxine undergoes extensive presystemic metabolism in the
liver. The primary metabolite of venlafaxine is ODV, but venlafaxine is also metabolised
to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In
vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the
formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in
vitro studies have been confirmed in a clinical study with subjects who are CYP2D6-poor
and -extensive metabolisers. However, despite the metabolic differences between the
CYP2D6-poor and -extensive metabolisers the total exposure to the sum of the two active
species (venlafaxine and ODV) was similar in the two metaboliser groups. Therefore,
CYP2D6-poor and -extensive metabolisers can be treated with the same regimen of
venlafaxine (see Interactions with Other Medicines, CYP2D6 Inhibitors).
Excretion
Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours after
a single radio-labelled dose as either unchanged venlafaxine (5%), unconjugated ODV
(29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of
the radioactive dose is recovered within 72 hours. Therefore, renal elimination of
venlafaxine and its metabolites is the primary route of excretion.
Food-Drug Interactions
Administration of venlafaxine modified release capsules with food has no effect on the
absorption of venlafaxine or on the subsequent formation of ODV.
Subject age and sex do not significantly affect the pharmacokinetics of venlafaxine. A
20% reduction in clearance was noted for ODV in subjects over 60 years old; this was
probably caused by the decrease in renal function that typically occurs with aging.
In some patients with compensated hepatic cirrhosis, the pharmacokinetic disposition of
both venlafaxine and ODV was significantly altered. The reduction in both the
metabolism of venlafaxine and elimination of ODV resulted in higher plasma
concentrations of both venlafaxine and ODV.
In patients with moderate to severe impairment of renal function, the total clearance of
both venlafaxine and ODV was reduced, and t was prolonged. The reduction in total
½
clearance was most pronounced in subjects with creatinine clearance less than 30
mL/min.
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CLINICAL TRIALS
Use in Major Depression
Three double blind, placebo controlled trials, of up to 12 weeks duration, have examined
the clinical efficacy of modified release venlafaxine in the treatment of major depression.
One of these studies also incorporated an active comparator, paroxetine. These studies
showed venlafaxine to have greater efficacy than both placebo and paroxetine in reducing
depression.
Use in Generalised Anxiety Disorder
Five placebo-controlled trials were conducted to evaluate the efficacy of modified release
venlafaxine in the treatment of anxiety. Two trials were eight-week studies, utilizing
venlafaxine doses of 75 mg, 150 mg and 225 mg/day and of 75 mg and 150 mg/day. In
one of these, buspirone was found not to be significantly different to placebo or to
venlafaxine. However, venlafaxine was found to be superior to placebo. Two other trials
were the first eight-weeks of two long term studies, utilizing venlafaxine doses of 75 mg225 mg/day and of 37.5 mg, 75 mg and 150 mg/day.
Four studies demonstrated superiority of modified release venlafaxine over placebo on at
least five of the following efficacy scales: HAM-A total score, the HAM-A psychic
anxiety factor, the Hospital Anxiety and Depression (HAD) anxiety subscale, and the
CGI severity of illness scale, as well as the HAM-A anxious mood and tension item. Two
of these four studies continued for up to six months. These two studies, which utilized
venlafaxine doses of 75 mg–225 mg/day and 37.5 mg, 75 mg and 150 mg/day
demonstrated superiority of venlafaxine over placebo on the HAM-A total score, HAM-A
psychic anxiety factor, the HAD anxiety factor, and the CGI severity of illness scale, as
well as the HAM-A anxious mood item.
The fifth trial was a short-term (8-week) comparison of the efficacy of 2 fixed doses of
modified release venlafaxine (75 mg and 150 mg) with placebo and diazepam followed
by a comparison of the long-term (6-month) efficacy of modified release venlafaxine and
placebo in the prevention of relapse. The most important results were the primary
efficacy variables at week 8 using an LOCF analysis. These demonstrated no significant
differences between either venlafaxine and placebo, or diazepam and placebo for any of
the primary efficacy variables. In view of this failure to demonstrate any effectiveness of
either venlafaxine or diazepam over placebo, the long-term outcomes of this study are not
of clinical or theoretical value. In conclusion, this study showed no anxiolytic effect of
either diazepam or placebo in the short-term (8 week phase).
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Modified Release Venlafaxine Table 1 Baseline and final mean HAM‐A total and CGI severity scores for placebo controlled GAD studies Study number HAM‐A Total CGI Severity treatment n Baseline Final n Baseline Final 210 (8 week study) Placebo 96 24.1 14.7 96 4.4 3.2 Venlafaxine (mg) 75 86 24.7 13.5 86 4.5 3.0 150
81
24.5
12.3
81
4.5
2.9
225 86 98 87 87 93 123 115 96 181 169 89 129 138 130 131 23.6 23.7 23.7 23.0 23.8 24.9 25.0 27.7 28.0 28.0 28.4 26.7 26.6 26.3 26.3 11.9 15.4 13.0 13.6 14.3 16.2 11.6 15.1 12.8 14.2 13.5 15.6 12.6 10.4 9.5 86 98 87 87 93 123 115 89 160 146 79 129 138 129 131 4.4 4.3 4.2 4.2 4.2 4.4 4.4 4.8 4.9 4.9 4.8 4.6 4.4 4.4 4.6 2.8 3.3 2.8 3.0 3.2 3.5 2.7 3.2 2.9 3.1 2.9 3.2 2.6 2.4 2.2 214 (8 week study) Placebo Venlafaxine (mg) 75 150 Buspirone 218 (6 month study) Placebo Venlafaxine (mg) 75‐225 377 (8 week period) Placebo Venlafaxine (mg) 75 150 Diazepam 378 (6 month study) Placebo Venlafaxine (mg) 37.5 75 150 Depression Relapse/Recurrence
A long-term study of depressed outpatients who had responded to modified release
venlafaxine during an initial 8-week open-label treatment phase and were randomly
assigned to continuation on venlafaxine or placebo for 6 months demonstrated a
significantly lower relapse rate for patients taking venlafaxine compared with those on
placebo.
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In a second long-term study, outpatients with a history of recurrent depression who had
responded to immediate-release venlafaxine by 8 weeks and maintained improvement
during an initial 6-month open-label treatment phase were randomly assigned to
maintenance therapy on venlafaxine or placebo for 12 months. Significantly fewer
patients taking venlafaxine compared with those on placebo had a reappearance of
depression.
Social Anxiety Disorder
The efficacy of modified release venlafaxine as a treatment for social anxiety disorder
(also known as social phobia) was established in four double-blind, parallel-group, 12week, multi-centre, placebo-controlled, flexible-dose studies and one double-blind,
parallel-group, 6-month, fixed/flexible-dose study in adult outpatients meeting DSM-IV
criteria for Social Anxiety Disorder. Patients received doses in a range of 75-225 mg/day.
Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). The LSAS
measures the relationship of impairment because of social anxiety disorder symptoms by
evaluating a patient's fear and avoidance in a broad range of situations (i.e., 13
performance and 11 social interaction situations). Psychometric studies have shown the
LSAS to be a valid and reliable measure of social anxiety.1 The LSAS scale has also been
shown to be sensitive to differences between active and placebo treatments.2
The results of these trials are presented in the table below. In these five trials, venlafaxine
was significantly more effective than placebo on change from baseline to endpoint on the
LSAS total score.
1
Clark, et al. Systematic assessment of social phobia in clinical practice. Depress and Anxiety 1997;6:47-61
Davidson JRT, et al. Treatment of social phobia with clonazepam and placebo. J Clin Psychopharmacol.
1993;13:423-428
2
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Modified Release Venlafaxine Table 2 Summary of results for primary efficacy variable in ITT patients at final on therapy visit: 12 week and 6 month Adjusted mean Adjusted change final on Raw Variable p Value from therapy baseline No. of Study number vs baseline score score patients Treatment group placebo Short‐term (12 week) studies LSAS Study 1 Placebo 138 86.7 69.0 ‐19.9 Venlafaxine a 133 91.1 57.8 ‐31.0 < 0.001 Study 2b Placebo 135 87.4 66.9 ‐22.1 Venlafaxine a 126 90.8 56.3 ‐32.8 0.003 Study 3 Placebo 132 83.6 64.5 ‐19.1 Venlafaxine a 129 83.2 47.6 ‐36.0 < 0.001 Paroxetinec 128 83.9 48.1 ‐35.4 < 0.001 Study 4 Placebo 144 86.1 64.3 ‐22.2 Venlafaxine 133 86.2 51.5 ‐35.0 Paroxetine 136 87.2 47.3 ‐39.2 Long‐term (6 month) study LSAS Study 5 Placebo 126 89.3 65.6 ‐23.5 Venlafaxine (total)d 238 89.0 51.2 ‐37.8 < 0.001 Venlafaxine 75 mg 119 91.8 51.0 ‐38.1 < 0.001 Venlafaxine 150‐225 mg 119 86.2 51.5 ‐37.6 < 0.001 a: Flexible dose range for venlafaxine was 75‐225 mg/day; b: Data shown are for ITT population; c: Flexible dose range for paroxetine was 20‐50 mg/day; d: Primary treatment group. ITT: intent to treat; LSAS: Liebowitz Social Anxiety Scale Panic Disorder
The efficacy of modified release capsules as a treatment for panic disorder was
established in two double-blind, 12-week, multicentre, placebo-controlled studies in adult
outpatients meeting DSM-IV criteria for panic disorder, with or without agoraphobia.
Patients received fixed doses of 75 or 150 mg/day in one study (Study 1) and 75 or 225
mg/day in the other study (Study 2).
In one flexible-dose study (Study 3) (75 mg to 225 mg daily doses), the primary outcome,
the percentage of patients free of full-symptom panic attacks, approached significance
(p=0.056). In this study, venlafaxine was significantly more effective than placebo for the
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two key secondary outcomes, (1) mean change from baseline to endpoint on the Panic
Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as
responders (much improved or very much improved) in the Clinical Global Impressions
(CGI) Improvement scale.
In another flexible-dose study (Study 4) (dose range 75 mg to 225 mg per day), modified
release venlafaxine was not significantly more effective than placebo for the primary
outcome, the percentage of patients free of full-symptom panic attacks, but it was
significantly more effective than placebo for the secondary outcome, percentage of
patients rated as responders (much improved or very much improved) in the Clinical
Impressions (CGI) Improvement scale.
Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of
patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale
(PAAS), (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale
(PDSS) total score, and (3) percentage of patients rated as responders (much improved or
very much improved) in the Clinical Global Impressions (CGI) Improvement scale. In
Studies 1 and 2, venlafaxine was significantly more effective than placebo in all three
variables.
Modified Release Venlafaxine Table 3 Primary efficacy variable PAAS: percent of patients free of full symptom panic attacks, final on therapy (12 weeks in studies 1 and 2, 10 weeks in studies 3 and 4), ITT population p‐Value Number (%) versus Study Treatment n panic free placeboa 1 Placebo 154 53(34.4) Venlafaxine 75mg 157 85(54.1) < 0.001 Venlafaxine 150mg 158 97(61.4) < 0.001 Paroxetine 160 96(60.0) < 0.001 2 Placebo 157 73(46.5) Venlafaxine 75mg 156 100(64.1) < 0.001 Venlafaxine 225mg 160 112(70.0) < 0.001 Paroxetine 151 89(58.9) 0.008 3 Placebo 155 63(40.6) Venlafaxine 75‐225mg 155 79(51.0) 0.056 4b Placebo 168 88(52.4) Venlafaxine 75‐225mg 160 88(55.0) 0.622 PAAS = Panic and Anticipatory Anxiety Scale; ITT = intent to treat
a Chi‐square p‐values obtained from logistic regression model logit (response) = treatment + center in studies 1, 3 and 4 and logistic regression model logit (response) = baseline + treatment + center in study 2 b excluding site 39127 Examination of subsets of the population studied did not reveal any differential
responsiveness on the basis of gender. There was insufficient information to determine
the effect of age or race on outcome in these studies.
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In a longer-term study (Study 5), adult outpatients meeting DSM-IV criteria for panic
disorder who had responded during a 12-week open phase with modified release
venlafaxine (75 to 225 mg/day) were randomly assigned to continue the same venlafaxine
dose (75, 150, or 225 mg) or switch to placebo for observation for relapse during a 6month double-blind phase. Response during the open phase was defined as >1 fullsymptom panic attack per week during the last 2 weeks of the open phase and a CGI
Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the
double-blind phase was defined as having 2 or more full-symptom panic attacks per week
for 2 consecutive weeks or having discontinued due to loss of effectiveness. Patients
receiving continued venlafaxine treatment experienced significantly lower relapse rates
over the subsequent 6 months compared with those receiving placebo.
Modified Release Venlafaxine Table 4 Survival analysis for relapse of panic disorder, ITT patients, double blind period Cumulative Number of Number of probability of Therapy group patients relapse (%) relapse Placebo 80 40(50.0) 0.523 Venlafaxine 89 20(22.5) 0.239 a p‐Values obtained from log‐ranked statistics of Kaplan‐Meier survival model p‐Valuea < 0.001 INDICATIONS
Elaxine SR is indicated for the treatment of:
•
Major Depression, including prevention of relapse and recurrence where
appropriate;

Generalised Anxiety disorder;
•
Social Anxiety Disorder;
•
Panic Disorder, including prevention of relapse.
•
CONTRAINDICATIONS
Hypersensitivity to venlafaxine or any excipients in the formulation
Concomitant use of venlafaxine and any monoamine oxidase inhibitor (MAOI) is
contraindicated. Venlafaxine must not be initiated for at least 14 days after
discontinuation of treatment with a MAOI. Venlafaxine must be discontinued for at least
7 days before starting treatment with any MAOI (See INTERACTION WITH OTHER
MEDICINES).
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PRECAUTIONS
Clinical Worsening and Suicide Risk
Patients with major depression, both adult and paediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or
unusual changes in behaviour, whether or not they are taking antidepressant medications,
and this risk may persist until significant remission occurs. Suicide is a known risk of
depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. Antidepressants may have a role in inducing worsening of
depression and the emergence of suicidality in certain patients during the early phases of
treatment. As improvement may not occur during the first few weeks or more of
treatment, patients should be monitored appropriately and observed closely for clinical
worsening and suicidality, especially at the beginning of a course of treatment or at the
time of dose changes, either increases or decreases.
Pooled analyses of short-term placebo-controlled trials of antidepressant medicines
(SSRIs and others) showed that these medicines increase the risk of suicidality in
children, adolescents, and young adults (ages 18-24 years) with major depression and
other psychiatric disorders. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond the age of 24
years; there was a reduction in the risk of suicidality with antidepressants compared to
placebo in adults age 65 years and older.
The pooled analysis of placebo-controlled trials in children and adolescents with major
depression, obsessive compulsive disorder, or other psychiatric disorders included a total
of 24 short-term trials of nine antidepressant medicines in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with major depression or other psychiatric
disorders included a total of 295 short-term trials (median duration 2 months) of 11
antidepressant medicines in over 77,000 patients. There was considerable variation in risk
of suicidality among medicines, but a tendency toward an increase in the younger patients
for almost all medicines studied. There were differences in absolute risk of suicidality
across the different indications, with the highest incidence with major depression.
No suicides occurred in any of the paediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about the medicine effect on
suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several
months. However, there is substantial evidence from placebo-controlled maintenance
trials in adults with depression that the use of antidepressants can delay the recurrence of
depression.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse or whose
emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting
symptoms (see also Abrupt Discontinuation of venlafaxine).
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It is particularly important that appropriate monitoring be undertaken during the initial
course of antidepressant treatment or at times of dose increase or decrease.
Patients with co-morbid depression associated with other psychiatric disorders being
treated with antidepressants should be similarly observed for clinical worsening and
suicidality.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility
(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and
mania, have been reported in adults, adolescents and children being treated with
antidepressants for major depression as well as for other indications, both psychiatric and
non-psychiatric. Although a causal link between the emergence of such symptoms and
either worsening of depression and /or emergence of suicidal impulses has not been
established, there is concern that such symptoms may be precursors of emerging
suicidality.
Prescriptions for Elaxine SR should be written for the smallest quantity of capsules
consistent with good patient management in order to reduce the possibility of overdosage.
This is particularly so at the times of treatment initiation or dosage change. Events
reported in overdose include electrocardiogram changes (QRS prolongation, QT
prolongation), cardiac arrhythmias (ventricular fibrillation; ventricular tachycardia,
including torsade de pointes), convulsions, and death (see OVERDOSAGE).
Information for Patients and Caregivers
Patients, their families and their caregivers should be alerted about the need to monitor
for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behaviour, worsening of depression, and suicidal ideation,
especially when initiating therapy or during any change in dose. Such symptoms should
be reported to the patient’s doctor, especially if they are severe, abrupt in onset, or were
not part of the patient’s presenting symptoms (see also Use in Children and
Adolescents).
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions
As with other serotonergic agents the development of a potentially life threatening
serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction, may occur
with venlafaxine treatment, particularly with concomitant use of other serotonergic drugs
(including SSRIs, SNRIs and triptans), with drugs that impair metabolism of serotonin
(including MAOIs such as methylene blue), or with antipsychotics or other dopamine
antagonists. Serotonin syndrome symptoms may include mental status changes (eg
agitation, confusion, hallucinations, and coma), autonomic instability (eg diaphoresis,
tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg
hyperreflexia, incooordination, myoclonus, tremor), and/or gastrointestinal symptoms (eg
nausea, vomiting and diarrhoea). Seratonin syndrome, in its most severe form, can
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resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with
possible rapid fluctuation of vital signs, and mental status changes.
If concomitant treatment with venlafaxine and other agents that may affect the
serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation and
dose increases.
Treatment with venlafaxine should be discontinued if serotonin syndrome or NMS-like
reactions occur and supportive symptomatic treatment initiated.
The concomitant use of venlafaxine with serotonin precursors (such as tryptophan
supplements) is not recommended.
Mydriasis
Mydriasis may occur in association with venlafaxine. It is recommended that patients
with raised intra-ocular pressure or patients at risk for acute narrow-angle glaucoma
(angle closure glaucoma) should be closely monitored.
Use in Patients with Renal Impairment
The total daily dose of venlafaxine must be reduced by 25% to 50% for patients with
renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/min.
The total daily dose of venlafaxine must be reduced by 50% in haemodialysis patients.
Because of individual variability in clearance in these patients, individualisation of
dosage may be desirable.
Use in Patients with Hepatic Impairment
The total daily dose of venlafaxine must be reduced by 50% in patients with mild to
moderate hepatic impairment. Reductions of more than 50% may be appropriate for some
patients.
Because of individual variability in clearance in these patients, individualisation of
dosage may be desirable.
Sustained Hypertension
Dose-related increases in blood pressure have been reported in some patients treated with
venlafaxine.
Among patients treated with 75 to 375 mg per day of modified release venlafaxine in premarketing depression studies, 3% (19/705) experienced sustained hypertension [defined
as treatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mm Hg and ≥ 10 mm
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Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5
to 225 mg per day of modified release venlafaxine in pre-marketing GAD studies, 0.5%
(5/1011) experienced sustained hypertension. Experience with the immediate-release
venlafaxine showed that sustained hypertension was dose-related, increasing from 3 to
7% at 100 to 300 mg per day to 13% at doses above 300 mg per day. An insufficient
number of patients received mean doses of modified release venlafaxine over 300 mg per
day to fully evaluate the incidence of sustained increases in blood pressure at these higher
doses.
In placebo-controlled pre-marketing depression studies with modified release venlafaxine
75 to 225 mg per day, a final on-drug mean increase in supine diastolic blood pressure
(SDBP) of 1.2 mm Hg was observed for treated patients compared with a mean decrease
of 0.2 mm Hg for placebo-treated patients. In placebo-controlled pre-marketing GAD
studies with modified release venlafaxine 37.5 to 225 mg per day up to 8 weeks or up to
6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for treated
patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebotreated patients. In pre-marketing Social Anxiety Disorder studies up to 12 weeks, the
final on-therapy mean change from baseline in SDBP was small - an increase of 0.78 mm
Hg, compared to a decrease of 1.41 mm Hg in placebo-treated patients. In a 6-month
study, the final on-therapy mean increase from baseline in SDBP with modified release
venlafaxine 150 to 225 mg was 1.49 mm Hg. The increase was significantly different
from the 0.6 mm Hg decrease with placebo and the 0.2 mm Hg decrease with venlafaxine
75 mg.
In pre-marketing depression studies, 0.7% (5/705) of the modified release venlafaxine
treated patients discontinued treatment because of elevated blood pressure. Among these
patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg,
SDBP). In pre-marketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381)
and 1.3% (7/535) of the modified release venlafaxine treated patients, respectively,
discontinued treatment because of elevated blood pressure. Among these patients, most
of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8
weeks; 8 to 28 mm Hg up to 6 months).
Cases of elevated blood pressure requiring immediate treatment have been reported in
post-marketing experience.
Sustained increases of SDBP could have adverse consequences. Therefore it is
recommended that patients receiving venlafaxine have regular monitoring of blood
pressure. For patients who experience a sustained increase in blood pressure while
receiving venlafaxine, either dose reduction or discontinuation should be considered. Preexisting hypertension should be controlled before treatment with venlafaxine. Caution
should be exercised in patients whose underlying conditions might be compromised by
increases in blood pressure.
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Increase in Serum Cholesterol
Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine
immediate release tablet-treated patients and 0.0% of placebo-treated patients for at least
3 months in placebo-controlled clinical trials.
Treatment with modified release venlafaxine for up to 12 weeks in pre-marketing
placebo-controlled depression trials was associated with a mean final on-therapy increase
in serum cholesterol concentration of approximately 0.039 mmol/L (1.5 mg/dL).
Modified release venlafaxine treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy
increases in serum cholesterol concentration of approximately 0.026 mmol/L (1.0 mg/dL)
and 0.059 mmol/L (2.3 mg/dL), respectively.
In the 12 week Social Anxiety Disorder studies, small mean increases in fasting levels of
total cholesterol (0.20 mmol/L, 4%) were seen in the modified release venlafaxine-treated
group at the final on-therapy evaluation; the increases were significantly different from
the changes in the placebo group. In a 6-month study, the final on-therapy mean increase
in total cholesterol was higher (0.32 mmol/L, 7%) in the venlafaxine 150 to 225 mg
group; however the total cholesterol value was only slightly increased (0.01 mmol/L) for
the venlafaxine 75mg group.
There were also significant mean increases from baseline in LDL, but not HDL for the
venlafaxine 150 to 225 mg group. The final on-therapy increase of 0.213 mmol/L from
baseline in LDL with venlafaxine 150 to 225 mg was significantly different from the
small decrease with placebo (0.079 mmol/L) and the negligible increase with venlafaxine
75mg (0.006 mmol/L).
Measurement of serum cholesterol levels should be considered during long-term
treatment.
Hyponatraemia
Cases of hyponatraemia, and/or the Syndrome of Inappropriate Antidiuretic Hormone
secretion (SIADH) may occur with venlafaxine, usually in volume-depleted or
dehydrated patients. Elderly patients, patients taking diuretics and patients who are
otherwise volume depleted, may be at greater risk for this event.
Caution is advised in administering venlafaxine to patients with diseases or conditions
that could affect haemodynamic responses or metabolism.
Use in Patients with Pre-Existing Heart Disease
Patients with a recent history of myocardial infarction or unstable heart disease were
excluded from all venlafaxine clinical trials. However, patients with other pre-existing
heart disease were not excluded, although they were neither separately analysed nor
systematically studied.
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Venlafaxine should be used with caution in patients with unstable heart disease (eg
myocardial infarction; significant left ventricular dysfunction, ventricular arrhythmia). In
these patients, assessment of the cardiovascular system (eg ECG; serum electrolytes
during diuretic treatment) should be considered during treatment with venlafaxine,
particularly when the dose is increased beyond 150-200 mg daily.
Evaluation of the electrocardiograms for 769 patients who received immediate release
venlafaxine in 4 to 6-week double blind, placebo-controlled trials showed that the
incidence of trial-emergent conduction abnormalities did not differ from that with
placebo.
The electrocardiograms for patients who received modified release venlafaxine or
placebo in the depression GAD and Social Anxiety Disorder trials were analysed. The
mean change from baseline in corrected QT interval (QTc) for venlafaxine treated
patients in depression studies was increased relative to that for placebo-treated patients
(increase of 4.7 msec for venlafaxine and decrease of 1.9 msec for placebo). The mean
change from baseline QTc for venlafaxine treated patients in the GAD studies did not
differ significantly from placebo. The final on-therapy mean increase from baseline in
QTc (3 msec) was significant for venlafaxine treated patients in the Social Anxiety
Disorder short-term studies. In the 6 month study, the final on-therapy mean increase
from baseline in QTc with venlafaxine 150 to 225 mg (3 msec) was significant, but the
increase was not significantly different from the small mean increase (0.5 msec) with
placebo. The value for venlafaxine 75mg was a 0.05 msec decrease.
Increases in heart rate may occur, particularly with higher doses. Therefore caution is
advised in patients whose underlying conditions may be compromised by increases in
heart rate.
The mean change from baseline in heart rate for modified release venlafaxine treated
patients in both the GAD and depression studies was significantly higher than for placebo
(a mean increase of 3-4 beats per minute for venlafaxine and 0-1 beat per minute for
placebo in the GAD and depression studies respectively). In the pooled short-term Social
Anxiety Disorder studies, the final on-therapy mean increase from baseline in heart rate
with venlafaxine was 5 beats per minute. In the 6 month study, the final on-therapy mean
increases from baseline in heart rate were significant with venlafaxine 75 (2 beats per
minute) and venlafaxine 150 to 225 mg (6 beats per minute); however only the increase
with the higher dose was significantly different from the small increase with placebo (0.4
beats per minute). The clinical significance of these changes is unknown.
Abrupt Discontinuation of venlafaxine
Discontinuation effects are well known to occur with antidepressants. Discontinuation
symptoms have been assessed both in patients with depression and in those with anxiety.
Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has
been found to be associated with the appearance of new symptoms, the frequency of
which increased with increased dose level and with longer duration of treatment.
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Symptoms reported included agitation, anorexia, anxiety, confusion, dry mouth, fatigue,
paraesthesias, vertigo, hypomania, nausea, vomiting, dizziness, convulsion, headache,
diarrhoea, sleep disturbance, insomnia, somnolence, sweating and nervousness. Where
such symptoms occurred, they were usually self-limiting, but in a few patients lasted for
several weeks.
Discontinuation effects were systematically studied in a long-term fixed-dose trial for
generalised anxiety disorder; 24% and 11% of patients recorded the appearance of at least
three withdrawal symptoms on abrupt discontinuation from 150 mg or 75 mg venlafaxine
once daily, respectively, compared with 3% for placebo. The most commonly reported
withdrawal symptoms on abrupt discontinuation were nausea, vomiting, dizziness,
lightheadedness, and tinnitus from 150mg venlafaxine once daily, and dizziness from
75mg venlafaxine once daily.
In this study, severe withdrawal reactions were observed in 1.3% of patients
discontinuing from 75 mg once daily (no patients requiring further drug treatment).
There is also a report of a withdrawal syndrome, confirmed by two challenges in a 32year-old woman who had received venlafaxine 300 mg daily for 8 months. It is,
therefore, recommended that the dosage of modified release venlafaxine be tapered
gradually and the patient monitored. The period required for discontinuation may depend
on the dose, duration of therapy and the individual patient (See DOSAGE AND
ADMINISTRATION and ADVERSE EFFECTS).
Altered Weight
Weight changes, either losses or gains, do not appear to present a clinically important
feature of venlafaxine treatment. Clinically significant weight gain or loss was seen in
less than 1% of patients treated with venlafaxine during clinical trials. A dose-dependent
weight loss (mean loss <1 kg) was noted in some patients treated with venlafaxine during
the first few months of venlafaxine treatment. After month 9, the mean weight began to
increase slightly but significantly, an effect often seen with tricyclic antidepressant
therapy. Significant weight loss (> 7 kg) was seen in 6 (0.3%) of 2,181 patients,
compared to no patients treated with placebo and 0.2% of patients treated with a
comparative antidepressant.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents,
including phentermine, have not been established. Co-administration of venlafaxine and
weight loss agents is not recommended. Elaxine SR is not indicated for weight loss alone
or in combination with other products.
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Seizures
Seizures have been reported with venlafaxine therapy and in overdose. Elaxine SR, as
with all antidepressants, should be introduced with care, in patients with a history of
seizure disorders. Elaxine SR should be discontinued in any patient who develops
seizures (see OVERDOSAGE).
Mania/Hypomania and Bipolar Disorder
Mania/hypomania may occur in a small proportion of patients with mood disorders
treated with antidepressants, including venlafaxine.
A major depressive episode may be the initial presentation of bipolar disorder. It is
generally believed (although not established in controlled trials) that treating such an
episode with an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be
adequately screened to determine if they are at risk for bipolar disorder; such screening
should include a detailed psychiatric history, including a family history of suicide, bipolar
disorder, and depression. It should be noted that Elaxine SR is not approved for use in
treating bipolar depression.
Aggression may occur in a small proportion of patients who have received
antidepressants, including venlafaxine treatment, dose reduction or discontinuation.
Venlafaxine should be used cautiously in patients with a history of aggression.
Skin/Allergic Reactions
Patients should be advised to notify their physician if they develop a rash, hives, or
related allergic phenomena.
Skin and Mucous Membrane Bleeding
Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The
risk of skin and mucous membrane bleeding may be increased in patients taking
venlafaxine, particularly if predisposed to such events. Venlafaxine should be used
cautiously in patients predisposed to bleeding including patients on anticoagulants and
platelets inhibitors.
Effects on Cognitive and Motor Performance
Although venlafaxine has been shown not to affect psychomotor, cognitive or complex
behaviour performance in healthy volunteers, any psychoactive medication may impair
judgment, thinking or motor skills, and patients should be cautioned about operating
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hazardous machinery, including automobiles, until they are reasonably certain that the
treatment does not affect them adversely.
Physical and Psychological Dependence
Clinical studies have shown no evidence of drug-seeking behaviour, development of
tolerance, or dose escalation over time among patients taking venlafaxine. Consequently,
physicians should carefully evaluate patients for a history of drug abuse and follow such
patients closely observing them for signs of misuse or abuse of venlafaxine (e.g.
development of tolerance, increase in dose, drug-seeking behaviour) (see
PHARMACOLOGY).
Use in Elderly Patients
No overall differences in effectiveness or safety were observed between elderly (aged 65
years and older) and younger patients. Modified release venlafaxine does not appear to
pose any exceptional safety problems for healthy elderly patients.
Effectiveness in elderly patients with social anxiety disorder has not been established.
Use in Children and Adolescents
Elaxine SR is not indicated for use in children and adolescents below 18 years of age as
safety and effectiveness has not been demonstrated. Therefore, Elaxine SR should not be
used in this age group.
In paediatric clinical trials, there were increased reports of hostility and, especially in
major depressive disorder, suicide-related events such as suicidal ideation and self-harm
(see also Clinical Worsening and Suicide Risk and ADVERSE EFFECTS).
As with adults, decreased appetite, weight loss, increased blood pressure and increased
serum cholesterol have been observed in children and adolescents aged 6 to 17 years (see
ADVERSE EFFECTS).
Use in Pregnancy
Category: B2
The safety of venlafaxine in human pregnancy has not been established. There are no
adequate and well-controlled studies in pregnant women. Venlafaxine must only be
administered to pregnant women if the expected benefits outweigh the possible risks.
Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy. If venlafaxine is used until or shortly before birth,
discontinuation effects in the newborn should be considered.
Some neonates exposed to venlafaxine, other SNRIs (Serotonin and Noradrenaline
Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third
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trimester have developed complications requiring prolonged hospitalisation, respiratory
support, or tube feeding. Such complications can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures,
temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia,
hypertonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These
features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a
drug discontinuation syndrome.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in
late pregnancy, may increase the risk of persistent pulmonary hypertension in the new
born (PPHN). Although no studies have investigated an association of PPHN to SNRI
treatment, this potential risk cannot be ruled out with venlafaxine taking into account the
related mechanism of action (inhibition of the re-uptake of serotonin).
In a rat teratology study, venlafaxine was given orally at dosages up to 80 mg/kg/day
(approximately 11 times the maximum recommended human dose). Foetotoxicity
evidenced by growth retardation was slightly increased at 80 mg/kg/day, an effect that
may be related to maternal toxicity at this dose level. Foetal survival and morphologic
development were not affected. In another teratology study, rabbits were given
venlafaxine dosages up to 90 mg/kg/day. Foetotoxicity evidenced by resorption and
foetal loss was slightly increased at 90 mg/kg/day (approximately 12 times the maximum
recommended human dose). These effects could be correlated with maternal toxicity. No
venlafaxine-associated teratogenic effect was noted in either species at any dosage,
though there was an increased incidence of 'W'-shaped apex of the heart in the rabbit
study. In these studies, animal exposure to the main human metabolite ODV was less,
and estimated exposure to venlafaxine was approximately 6-fold more than would be
expected in humans taking the recommended therapeutic and maximum doses. In rats,
estimated exposure to venlafaxine was more than the expected human exposure. No
teratogenic effect was seen.
In a perinatal toxicity study in rats after oral dosing of dams with 30 mg/kg or more,
decreased pup survival following birth was observed. This effect is secondary to
treatment-decreased maternal care, and is also seen with other antidepressants.
Use in Lactation
Venlafaxine and/or its metabolites are secreted in milk of lactating rats at concentrations
higher than those found in the plasma of the dam. Venlafaxine and its metabolites have
been shown to pass into human milk. The total dose of venlafaxine and Odesmethylvenlafaxine ingested by breast fed infants can be as high as 9.2% of maternal
intake. Therefore, the use of Elaxine SR in nursing women cannot be recommended.
Exposed infants should be observed closely.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Reproduction and fertility studies in rats showed no effects on male or female fertility at
2
oral doses of up to 2 times the maximum recommended human dose on a mg/m basis.
Reduced fertility was observed in a study in which both male and female rats were
exposed to the major metabolite of venlafaxine (ODV). This exposure was approximately
2 to 3 times that of a human venlafaxine dose of 225 mg/day. The human relevance of
this finding is unknown.
Venlafaxine was given by oral gavage to mice and rats for 18 months and 24 months
respectively, at dosages up to 120 mg/kg/day. There were no clear drug-related oncogenic
effects in either species. In these studies, animal exposure to the main human metabolite
ODV was less, and exposure to venlafaxine was more than would be expected in humans
taking the recommended therapeutic and maximum doses.
There was no evidence of gene mutation or chromosomal change in a series of
genotoxicity assays using venlafaxine and the main human metabolite ODV.
Signs of pharmacological toxicity were seen in paternal and maternal rats given
venlafaxine doses of 30 and 60 mg/kg/day, but no adverse effect was noted in fertility or
general reproductive performance. Decreased foetal size and pup weight at birth with 60
mg/kg/day may be correlated with maternal toxicity.
INTERACTIONS WITH OTHER MEDICINES
Venlafaxine and ODV are 27% and 30% bound to plasma proteins, respectively.
Therefore interactions due to protein binding of venlafaxine and the major metabolite are
not expected.
Monoamine oxidase inhibitors
Concomitant use with Elaxine SR is contraindicated.
Irreversible Monoamine Oxidase Inhibitors
Severe adverse reactions have been reported in patients who have recently been
discontinued from a MAOI and started on venlafaxine, or have recently had venlafaxine
therapy discontinued prior to initiation of a MAOI or when these two agents are coadministered. Reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting,
flushing, dizziness, hyperthermia with features resembling neuroleptic malignant
syndrome and/or serotonergic syndrome, seizures, and death. Do not use venlafaxine in
combination with a MAOI or within at least 14 days of discontinuing MAOI treatment.
Allow at least 7 days after stopping venlafaxine before starting a MAOI (see
CONTRAINDICATIONS).
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Reversible Monoamine Oxidase Inhibitors
Elaxine SR should not be administered concomitantly with moclobemide.
There are no clinical trials to support the recommendation of a specific time between
discontinuing treatment with the reversible MAOI, moclobemide and initiating
venlafaxine therapy or switching to moclobemide. Given the risk for adverse reactions
described for irreversible MAOIs (see above), an adequate washout period should be
ensured when switching a patient between venlafaxine and moclobemide. The
appropriate washout period should take into account the pharmacological properties of
venlafaxine and moclobemide and the clinician’s assessment of the individual patient.
Based on the half-lives of moclobemide, venlafaxine and ODV, the minimum washout
period should be 24 hours when switching from moclobemide to Elaxine SR and 7 days
when switching from Elaxine SR to moclobemide.
CNS Active Drugs
The risk of using venlafaxine in combination with other CNS-active drugs has not been
systematically evaluated. Consequently, caution is advised when venlafaxine is taken in
combination with other CNS-active drugs.
Serotonin Syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life threatening
condition, may occur with venlafaxine treatment, particularly with concomitant use of
other agents that may affect the serotonergic neurotransmitter system (including triptans,
SSRIs, other SNRIs, lithium, sibutramine, tramadol, or St John’s Wort [Hypericum
perforatum], with drugs which impair metabolism of serotonin (such as MAOIs,
including linezolid [an antibiotic which is a reversible non-selective MAOI] and
methylene blue) (see CONTRAINDICATIONS), or with serotonin precursors (such as
tryptophan supplements). Serotonin syndrome symptoms may include mental status
changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal
symptoms (see PRECAUTIONS).
Serotonin syndrome has been reported in association with concomitant use with selective
serotonin reuptake inhibitors (SSRIs). The decision to use venlafaxine in combination
with SSRIs should include the advice of a psychiatrist. If concomitant treatment of
venlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is
clinically warranted, careful observation of the patient is advised, particularly during
treatment initiation and dose increases. The concomitant use of venlafaxine with
serotonin precursors (such as tryptophan supplements) is not recommended.
As with other antidepressants, co-administration of venlafaxine and products containing
Hypericum perforatum (St. John's Wort) is not recommended due to possible
pharmacodynamic interactions.
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No information is available on the use of Elaxine SR in combination with opiates.
There have been reports of elevated clozapine levels in association with adverse events
including seizures, following the administration of venlafaxine.
Indinavir
A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36%
decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of
venlafaxine and ODV. The clinical significance of this interaction is unknown.
Warfarin
There have been reports of increases in prothrombin time, partial thromboplastin time, or
INR when venlafaxine was given to patients receiving warfarin therapy.
Ethanol
Venlafaxine has not been shown to increase the impairment of mental and motor skills
caused by ethanol. However, as with all CNS active drugs, patients should be advised to
avoid alcohol consumption while taking Elaxine SR.
Cimetidine
At steady-state cimetidine has been shown to inhibit the first-pass metabolism of
venlafaxine but had no apparent effect on the formation or elimination of ODV, which is
present in much greater quantity in the systemic circulation. The overall pharmacological
activity of venlafaxine plus ODV is expected to increase only slightly in most patients.
No dosage adjustment seems necessary when modified release venlafaxine is coadministered with cimetidine. However, for elderly patients or patients with hepatic
dysfunction, the interaction could potentially be more pronounced and for such patients
clinical monitoring is indicated when Elaxine SR is administered with cimetidine.
Diazepam
The pharmacokinetic profiles of venlafaxine and ODV were not altered when venlafaxine
and diazepam were administered together to healthy volunteers. Venlafaxine had no
effect on the pharmacokinetics of diazepam or affect the psychomotor and psychometric
effects induced by diazepam.
Lithium
The steady-state pharmacokinetics of venlafaxine and ODV are not affected when lithium
is co-administered. Venlafaxine also has no effect on the pharmacokinetics of lithium.
(See also CNS Active Drugs.) However, there have been reports of venlafaxine
interaction with lithium resulting in increased lithium levels.
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Haloperidol
Venlafaxine administered under steady-state conditions (75 mg twice daily) to 24 healthy
subjects decreased total oral clearance (Cl/F) of a single 2 mg dose of haloperidol by
42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol
Cmax increased 88% when co-administered with venlafaxine, but the haloperidol
elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is
unknown.
Metoprolol
Concomitant administration of venlafaxine (50mg every 8 hours for 5 days) and
metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a
pharmacokinetic interaction study for both drugs resulted in an increase of plasma
concentrations of metoprolol by approximately 30-40% without altering the plasma
concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the
pharmacokinetic profile of venlafaxine or its active metabolite, ODV.
Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this
study. Caution should be exercised with co-administration of venlafaxine and metoprolol.
Venlafaxine treatment has been associated with dose-related increases in blood pressure
in some patients. It is recommended that patients receiving Elaxine SR have regular
monitoring of blood pressure (see PRECAUTIONS – Sustained Hypertension).
Risperidone
Venlafaxine increased risperidone AUC by 32% but did not significantly alter the
pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Drugs Metabolised by Cytochrome P450 Isoenzymes
In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6 and
that venlafaxine does not inhibit CYP1A2, CYP2C9 or CYP3A4. Some of these findings
have been confirmed with drug interaction studies between venlafaxine and imipramine
(metabolised by CYP2D6) and diazepam (metabolised by CYP2C19). Therefore, Elaxine
SR is not expected to interact with other drugs metabolised by these isoenzymes.
Imipramine
Venlafaxine did not affect the CYP2D6-mediated 2-hydroxylation of imipramine or its
active metabolite, desimipramine, which indicates that venlafaxine does not inhibit the
CYP2D6 isoenzyme. However, the renal clearance of 2-hydroxydesimipramine was
reduced with co-administration of venlafaxine.
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Imipramine partially inhibited the CYP2D6-mediated formation of ODV, however, the
total concentrations of active compounds (venlafaxine plus ODV) was not affected with
imipramine administration. Additionally, in a clinical study involving CYP2D6-poor and
-extensive metabolisers, the total sum of the two active species (venlafaxine and ODV)
was similar in the two metaboliser groups. Therefore, no dosage adjustment is expected
when venlafaxine is co-administered with a CYP2D6 inhibitor. However, desipramine
AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. There was
an increase of 2-OH-desipramine AUC by 2.5 to 4.5 fold. The clinical significance of this
finding is unknown.
Potential for Other Drugs to Affect Venlafaxine
The metabolic pathways for venlafaxine include CYP2D6 and CYP3A4.
In vitro and in vivo studies indicate that venlafaxine is metabolised predominantly to its
active metabolite ODV by the cytochrome P450 enzyme CYP2D6, the isoenzyme that is
responsible for the genetic polymorphism seen in the metabolism of many
antidepressants. Therefore the potential exists for a drug interaction between drugs that
inhibit CYP2D6-mediated metabolism (such as amiodarone and quinidine) and
venlafaxine. CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of
venlafaxine.
CYP2D6 Inhibitors
Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of
venlafaxine to ODV, resulting in increased the plasma concentrations of venlafaxine and
decreased concentrations of ODV. As venlafaxine and ODV are both pharmacologically
active, no dosage adjustment is required when venlafaxine is co-administered with a
CYP2D6 inhibitor.
CYP3A4 Inhibitors.
Concomitant use of CYP3A4 inhibitors (such as erythromycin, fluconazole, ketoconazole
and grapefruit juice) and venlafaxine may increase levels of venlafaxine and ODV.
Therefore caution is advised when combining venlafaxine with a CYP3A4 inhibitor.
In vitro studies indicate that venlafaxine is likely metabolised to a minor, less active
metabolite, N-desmethylvenlafaxine, by CYP3A4. A pharmacokinetic study with
ketoconazole (a CYP3A4 inhibitor) in extensive (EM) and poor metabolisers (PM) of
CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in
subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in
EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in
EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects
and 70% in PM subjects. AUC values for ODV increased by 23% and 33% in EM and
PM subjects, respectively.
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CYP2D6 and 3A4 Inhibitors
The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both
CYP2D6 and CYP3A4, the primary metabolising enzymes for venlafaxine, has not been
studied. However, this concomitant use would be expected to increase venlafaxine
plasma concentrations. Therefore caution is advised if a patient’s therapy includes
venlafaxine and any agent(s) that produces simultaneous inhibition of these two enzyme
systems. In patients with unstable heart disease receiving these combinations, assessment
of the cardiovascular system (eg ECG; serum electrolytes during diuretic treatment)
should be considered during treatment with venlafaxine (see PRECAUTIONS - Use in
Patients with Pre-Existing Heart Disease).
Antihypertensive and Hypoglycaemic Agents
Retrospective analysis of study events occurring in patients taking venlafaxine
concurrently with antihypertensive or hypoglycaemic agents in clinical trials provided no
evidence suggesting incompatibility between treatment with venlafaxine and treatment
with either antihypertensive or hypoglycaemic agents.
Electroconvulsive Therapy
There are no clinical data establishing the benefit of Elaxine SR combined with
electroconvulsive therapy.
Effects on Laboratory Tests
No interference on laboratory tests by venlafaxine is known.
ADVERSE EFFECTS
Clinical Trials
The information included in the Adverse Effects clinical trials subsection are those that
were observed in short-term, placebo-controlled studies with venlafaxine and has been
based on data from a pool of three 8- and 12-week controlled clinical trials in Major
Depressive Disorder (dose range of 75 – 225 mg/day), on data up to 8 weeks from a pool
of five controlled clinical trial in Generalised Anxiety Disorder with venlafaxine (dose
range 37.5 – 225 mg/day), on data up to 12 weeks from a pool of five controlled clinical
trials in Social Anxiety Disorder (dose range of 75 – 225 mg/day), and on data up to 12
weeks from a pool of four controlled clinical trials in Panic Disorder (dose range 75 –
225 mg/day). (The adverse events occurring at an incidence ≥ 2% among venlafaxine
treated patients or at an incidence greater than the placebo treated patients are provided in
the table below). The table shows the percentage of patients in each group who had at
least one episode of an event at some time during the treatment. The prescriber should be
aware that these figures cannot be used to predict the incidence of side effects in the
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course of usual medical practice where patient characteristics and other factors differ
from those which prevailed in the clinical trials.
Adverse Event Incidence in Clinical Trials
Body System
Preferred term
Major Depressive
Disorder 1,5
Generalised Anxiety
Disorder 2
Social Anxiety
Disorder3
Panic Disorder4
Venlafaxine
n=357
Placebo
n=285
Venlafaxine
n=1381
Placebo
n=555
Venlafaxine
n=819
Placebo
n=695
Venlafaxine
n=1001
Placebo
n=662
Body as a whole
Headache
Asthenia
Abdominal Pain
Accidental Injury
8%
-
7%
-
12%
-
8%
-
38%
19%
6%
4%
34%
9%
4%
3%
10%
-
8%
-
Cardiovascular
Hypertension
Vasodilatation6
Palpitation
4%
4%
-
1%
2%
-
4%
-
2%
-
5%
3%
3%
3%
2%
1%
4%
3%
-
3%
2%
-
Digestive
Nausea
Constipation
Anorexia7
Vomiting
Diarrhoea
Dyspepsia
Flatulence
31%
8%
8%
4%
4%
12%
5%
4%
2%
3%
35%
10%
8%
5%
-
12%
4%
2%
3%
-
31%
9%
17%
3%
8%
7%
-
9%
3%
2%
2%
6%
6%
-
21%
9%
8%
-
14%
3%
3%
-
Metabolic/Nutritional
Weight loss
3%
0%
-
-
2%
<1%
-
-
Nervous
Dizziness
Somnolence
Insomnia
Dry Mouth
Nervousness
Abnormal drewams8
Tremor
Depression
Paraesthesia
Libido decreased
Agitation
Hypertonia
Anxiety
Twitching
20%
17%
17%
12%
10%
7%
5%
3%
3%
3%
3%
-
9%
8%
11%
6%
5%
2%
2%
<1%
1%
<1%
1%
-
16%
14%
15%
16%
6%
3%
4%
2%
4%
3%
-
11%
8%
10%
6%
4%
2%
<1%
1%
2%
2%
-
16%
20%
24%
17%
10%
3%
5%
8%
3%
5%
3%
8%
8%
8%
4%
5%
<1%
2%
2%
1%
4%
<1%
11%
12%
17%
12%
5%
4%
-
10%
6%
9%
6%
2%
2%
-
Respiratory
Pharyngitis
Yawning
7%
3%
6%
0%
3%
<1%
5%
<1%
-
-
Skin
Sweating
14%
3%
10%
3%
13%
4%
10%
2%
Special Senses
Abnormal Vision9
4%
<1%
5%
<1%
4%
2%
-
-
Urogenital
Abnormal Ejaculation10
Impotence11
16%
4%
<1%
<1%
11%
5%
<1%
<1%
19%
6%
<1%
<1%
8%
4%
<1%
<1%
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Orgasmic Dysfunction12
3%
<1%
2%
0%
5%
<1%
2%
<1%
1.
Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with venlafaxine, except
the following events which had an incidence of equal to or less than placebo: abdominal pain, accidental injury,
anxiety, back pain, bronchitis, diarrhoea, dysmenorrhoea, dyspepsia, flu syndrome, headache, infection, pain,
palpitation, rhinitis, and sinusitis.
2. Adverse events for which the venlafaxine reporting rate was less than or equal to the placebo rate are not included.
These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhoea, dysmenorrhoea, dyspepsia, flu
syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency.
3. Adverse events for which the venlafaxine reporting rate was less than or equal to the placebo rate are not included.
These events are: athralgia, back pain, dysmenorrhoea, flu syndrome, infection, pain, pharyngitis, rhinitis, and
upper respiratory tract infection.
4. Adverse events for which the venlafaxine reporting rate was less than or equal to the placebo rate are not included.
These events are: abdominal pain, abnormal vision, accidental injury, anxiety, back pain, diarrhoea,
dysmenorrhoea, dyspepsia, flu syndrome, headache, infection, nervousness, pain, paraesthesia, pharyngitis, rash,
rhinitis, and vomiting.
5. <1% indicates an incidence greater than zero but less than 1%.
6. Mostly “hot flushes”.
7. Mostly “decreased appetite” and “loss of appetite”
8. Mostly “vivid dreams”, “nightmare” and “increased dreaming”
9. Mostly “blurred vision” and “difficulty focussing eyes”
10. Males only – Mostly “delayed ejaculation”
11. Incidence is based on number of male patients
12. Females only – Mostly “delayed orgasm”, “abnormal orgasm” or “anorgasmia”
The following table lists adverse reactions from combined analyses of the clinical studies
for Major Depression, Generalised Anxiety Disorder, Social Anxiety Disorder, and Panic
Disorder. The adverse reactions have been presented using CIOMS frequency categories:
Common: >1%; Uncommon: >0.1% and <1%; Rare: >0.01% and <0.1%; Very rare: <0.01%.
Body System
Body As A Whole
Common:
Uncommon:
Very rare:
Cardiovascular
Common:
Uncommon:
Digestive
Common:
Uncommon:
Haematological/
Lymphatic
Uncommon:
Rare:
Metabolic/
Nutritional
Common:
Uncommon:
Rare:
Nervous
Common:
Adverse Reactions
Asthenia/fatigue.
Photosensitivity reaction.
Anaphylaxis.
Hypertension, vasodilatation (mostly hot flashes/flushes).
Hypotension, postural hypotension, syncope, tachycardia.
Appetite decreased, constipation, nausea, vomiting.
Bruxism.
Ecchymosis, mucous membrane bleeding.
Prolonged bleeding time, thrombocytopenia.
Serum cholesterol increased (particularly with prolonged administration
and with higher doses), weight loss.
Abnormal liver function tests, hyponatraemia, weight gain.
Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Abnormal dreams, decreased libido, dizziness, dry mouth, increased muscle
tonus, insomnia, nervousness, paraesthesia, sedation, tremor.
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Uncommon:
Rare:
Respiratory
Common:
Skin
Common:
Uncommon:
Special Senses
Common:
Urogenital
Common:
Uncommon:
Apathy, hallucinations, myoclonus.
Convulsion, manic reaction, neuroleptic malignant syndrome (NMS),
serotonergic syndrome.
Yawning.
Sweating.
Rash.
Abnormality of accommodation, mydriasis, visual disturbance.
Abnormal ejaculation/orgasm (males), anorgasmia, erectile dysfunction,
urination impaired (mostly hesitancy)
Abnormal orgasm (females), menorrhagia, urinary retention.
Post-Marketing Reports
The following table lists adverse reactions derived from post-marketing spontaneous
reports in patients with major depression, generalised anxiety disorder, social anxiety
disorder and panic disorder. Adverse reactions are shown in CIOMS frequency
categories: Common: >1%; Uncommon: >0.1% and <1%; Rare: >0.01% and <0.1%; Very rare:
<0.01%.
Body System
Body As A Whole
Common:
Uncommon:
Cardiovascular
Common:
Very rare:
Digestive
Uncommon:
Very rare:
Haematological/
Lymphatic
Uncommon:
Very rare:
Metabolic/
Nutritional
Rare:
Very rare:
Musculoskeletal
Very rare:
Nervous
Very common:
Common:
Adverse Reactions
Chills
Angioedema
Palpitations
QT prolongation, ventricular fibrillation, ventricular tachycardia (including
torsades de pointes)
Diarrhoea
Pancreatitis
Gastrointestinal bleeding
Blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia
and pancytopenia)
Hepatitis
Prolactin increased
Rhabdomyolysis
Headache
Confusion, depersonalisation
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Uncommon:
Rare:
Very rare:
Respiratory
Very rare:
Skin
Common:
Uncommon:
Very rare:
Frequency
unknown:
Special Senses
Uncommon:
Very rare:
Urogenital
Common:
Uncommon:
Rare:
Agitation, impaired coordination and balance
Akathisia/psychomotor restlessness
Delirium, extrapyramidal reactions (including dystonia, and dyskinesia),
tardive dyskinesia
Pulmonary cosinophilis
Night sweats
Alopecia
Erythema multiforme, Stevens-Johnson syndrome, pruritis, urticaria
Toxic epidermal necrolysis
Tinnitus
Angle closure glaucoma
Menstrual disorders associated with increased bleeding or increased
irregular bleeding (eg menorrhagia, metrorrhagia), urinary frequency
increased
Proteinuria
Urinary incontinence
Discontinuation effects are well known to occur with antidepressants, and it is therefore
recommended that the dosage is tapered gradually and the patient monitored (see
DOSAGE AND ADMINISTRATION). The following symptoms have been reported in
association with abrupt discontinuation or dose-reduction, or tapering of treatment:
hypomania, anxiety, agitation, nervousness, confusion, insomnia or other sleep
disturbances, fatigue, somnolence, paraesthesia, dizziness, convulsion, vertigo, headache,
tinnitus, impaired coordination and balance, sweating, dry mouth, anorexia, diarrhoea,
nausea, and vomiting. In premarketing studies, the majority of discontinuation reactions
were mild and resolved without treatment.
In the Social Anxiety Disorder pooled short-term studies, the most common taper/poststudy-emergent adverse events were dizziness (13%), nausea (7%), insomnia (3%),
nervousness (3%) and asthenia (2%). In the 6-month study, the most common taper/poststudy treatment emergent adverse events were dizziness (21% and 16%) and nausea (7%
and 10%) for modified release venlafaxine 75 mg and modified release venlafaxine 150225 mg, respectively.
Paediatric Patients (see PRECAUTIONS –Clinical Worsening and Suicide Risk and
Use In Children and Adolescents)
In general, the adverse reaction profile of venlafaxine in placebo-controlled clinical trials
in children and adolescents (aged 6 to 17) was similar to that seen for adults. As with
adults, decreased appetite, weight loss, increased blood pressure and increased serum
cholesterol were observed. Additionally, the following adverse reactions were observed:
abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and myalgia. In paediatric
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PI 120313A
clinical trials, there were increased reports of hostility and, especially in major
depression, suicide-related adverse events such as suicidal ideation and self-harm.
DOSAGE AND ADMINISTRATION
Usual Dose
The usual recommended dose for the treatment of major depression, generalised anxiety
disorder or social anxiety disorder is 75 mg per day given once daily. After two weeks,
the dose may be increased to 150 mg per day given once daily if further clinical
improvement is required. If needed, this can be increased up to 225 mg given once daily.
Dose increments should be made at intervals of approximately 2 weeks or more, but not
less than 4 days.
The recommended dose is based on results of clinical trials in which modified release
venlafaxine was mostly given once daily in doses from 75 to 225 mg. Antidepressant
activity with the 75 mg dose was observed after 2 weeks of treatment and anxiolytic
activity was observed after one week.
It is recommended that Elaxine SR be taken with food, at approximately the same time
each day. Each capsule must be swallowed whole with fluid. Do not divide, crush, chew,
or dissolve. Elaxine SR should be administered once daily,
Panic Disorder
The recommended dose is 75 mg of Elaxine SR once daily. Treatment should be started
with a dose of 37.5 mg per day of Elaxine SR for the first 4 to 7 days, after which the
dose should be increased to 75 mg once daily.
Patients not responding to the 75 mg/day dose may benefit from dose increases to a
maximum of 225 mg/day, although there is no direct clinical trial evidence of any
significant increase in efficacy with increase in dose. Dosage increases can be made in
increments of 75 mg per day at intervals of approximately 2 weeks or more, but not less
than 4 days.
Patients with Renal or Hepatic Impairment
Patients with renal and/or hepatic impairment should receive lower doses of Elaxine SR.
The total daily dose of venlafaxine must be reduced by 25% to 50% for patients with
renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/min.
Haemodialysis clearances of both venlafaxine and ODV in humans are low. The total
daily dose of venlafaxine must be reduced by 50% in haemodialysis patients.
Patients with mild to moderate hepatic impairment should also have their dosage reduced
by 50%. Further reductions in dosage should be considered for patients with more severe
degrees of hepatic impairment.
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PI 120313A
Because of individual variability in clearance in these patients, individualisation of
dosage may be desirable.
Elderly Patients
No adjustment in the usual dose is recommended for elderly patients solely because of
their age. As with any antidepressant, however, caution should be exercised in treating
the elderly. When individualising the dosage, extra care should be taken when increasing
the dose.
Maintenance/Continuation/Extended Treatment
The physician should periodically re-evaluate the usefulness of long-term modified
release venlafaxine treatment for the individual patient. It is generally agreed that acute
episodes of major depression require several months or longer of sustained
pharmacological therapy. Whether the dose of antidepressant needed to induce remission
is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Usually, the dosage for prevention of relapse or for prevention of recurrence of a new
episode is similar to that used during initial treatment. Patients should be regularly reassessed in order to evaluate the benefit of long-term therapy.
In Social Anxiety Disorder, continuing therapeutic benefit has been established for
periods of up to 6 months. The need for continuing medication in patients with Social
Anxiety Disorder who improve with venlafaxine treatment should be periodically
assessed.
It is generally agreed that acute episodes of panic disorder require several months or
longer of sustained pharmacological therapy beyond response to the acute episode.
Longer-term efficacy was demonstrated in one study (Study 5) in which patients
responding during 12 weeks of acute treatment with modified release venlafaxine were
assigned randomly to placebo or to the same dose of venlafaxine (75, 150, or 225
mg/day) during 6 months of maintenance treatment as they had received during the acute
stabilization phase (see CLINICAL TRIALS – Panic Disorder).
Discontinuing Elaxine SR
When Elaxine SR at a dose of 75 mg/day or greater has been administered for more than
1 week is stopped, it is recommended whenever possible that the dose be tapered
gradually to minimise the risk of discontinuation symptoms. In clinical trials with
modified release venlafaxine, tapering was achieved by reducing the daily dose by 75 mg
at 1 week intervals. To facilitate tapering below 75 mg of Elaxine SR, physicians may
consider prescribing the 37.5 mg capsules once daily (see also Usual Dosage above). The
period required for tapering may depend on the dose, duration of therapy, and the
individual patient. Patients should be advised to consult their physician before abruptly
discontinuing Elaxine SR.
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PI 120313A
OVERDOSAGE
In managing overdosage, consider the possibility of multiple medication involvement.
The physician should consider contacting a poison control centre on the treatment of any
overdose (See INTERACTIONS WITH OTHER MEDICINES).
During pre-marketing trials, most patients who have overdosed with venlafaxine were
asymptomatic. Of the remainder, somnolence was the most commonly reported
symptom. Mild sinus tachycardia and mydriasis have also been reported. There were no
reports of seizures, respiratory distress, significant cardiac disturbances, or significant
laboratory test result abnormalities among any of the cases reported to date. However,
seizures and respiratory distress occurred in one patient in an on-going study who
ingested an estimated 2.75g of venlafaxine with naproxen and thyroxine. Generalised
convulsions and coma resulted and emergency resuscitation was required. Recovery was
good without sequelae.
In post-marketing experience, overdose with venlafaxine was reported predominantly in
combination with alcohol and/or other drugs. The most commonly reported events in
overdose include tachycardia, changes in level of consciousness (ranging from
somnolence to coma), mydriasis, vomiting and seizures. Other events reported included
electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS
prolongation), ventricular fibrillation, ventricular tachycardia (including torsades de
pointes), bradycardia, hypotension, vertigo, and death. Serotonin toxicity has been
reported in association with venlafaxine overdose.
Published retrospective analyses from the United Kingdom (UK) report the rate of
antidepressant overdose deaths per million prescriptions. In these analyses, the rate for
venlafaxine is higher than that for SSRIs, but lower than that for tricyclic antidepressants.
These analyses did not adjust for suicide risk factors. Epidemiological studies have
shown that venlafaxine is prescribed to patients with a higher pre-existing burden of
suicide risk factors than patients prescribed SSRIs. The extent to which the finding of an
increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in
overdosage as opposed to some characteristics of venlafaxine-treated patients is not clear,
Prescriptions of venlafaxine should be written for the smallest quantity of drug consistent
with good patient management, in order to reduce the risk of overdose (see
PRECAUTIONS - Clinical Worsening and Suicide Risk).
Management of Overdosage
General supportive and symptomatic measures are recommended. Ensure an adequate
airway, oxygenation and ventilation. Cardiac rhythm and vital signs must be monitored.
Administration of activated charcoal may also limit drug absorption. Where there is a risk
of aspiration, induction of emesis is not recommended. No specific antidotes for
venlafaxine are known. Forced diuresis, dialysis, haemoperfusion and exchange
transfusion are unlikely to be of benefit. Venlafaxine and ODV are not considered
dialyzable because haemodialysis clearance of both compounds is low.
Page 33 of 34
PI 120313A
Contact the Poisons Information Centre on 131 126 for further advice on overdosage
management.
PRESENTATION AND STORAGE CONDITIONS
Elaxine SR 37.5, Elaxine SR 75 and Elaxine SR 150 venlafaxine (as hydrochloride)
modified release capsules are available for oral use as:
 37.5 mg, grey cap/peach body with thick and thin radial circular bands on the cap
and body in red ink (size 3 capsule).
 75 mg, peach cap and body with thick and thin radial circular bands on the cap
and body in red ink (size 1 capsule).
 150 mg, dark orange cap and body with thick and thin radial circular bands on the
cap and body in white ink (size 0 capsule).
Elaxine SR 37.5, Elaxine SR 75 and Elaxine SR 150 are packed in blisters
(PVC/PCTFE/Al or PVDC/PVC/Al), in cartons containing 28 capsules.
Store below 25°C.
POISON SCHEDULE OF THE MEDICINE
S4 - PRESCRIPTION ONLY MEDICINE
NAME AND ADDRESS OF THE SPONSOR
Spirit Pharmaceuticals Pty Ltd
117 Harrington St
The Rocks, Sydney NSW 2000
Australia
DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF
THERAPEUTIC GOODS (THE ARTG):
30 July 2010
DATE OF MOST RECENT AMENDMENT: 12 March 2013
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